Gamma Delta-T cells are a rare subpopulation of T lymphocytes with unique antitumor and antiviral properties making them ideal to study in the context of developing novel approaches to treat malignant or infectious diseases. Recent advances by ourselves and others have led to the development of the scientific rationale and the technical means necessary to perform early-phase human clinical trials designed to exploit the innate antitumor properties of Gamma Delta T-cells. Two general approaches are currently being taken in this regard, both relying upon either the in vivo activation or the ex vivo expansion (and subsequent re-infusion) of autologous (i.e., patient-derived) Gamma Delta-T cells. However, central to this proposal's rationale, new findings have now established that when compared to Gamma Delta-T cells found in healthy donors, Gamma Delta-T cells found in tumor-bearing hosts appear to be substantially diminished in number, or are functionally impaired in a variety of important ways. Objectives: We hypothesize that in the majority of tumor-bearing hosts, the Gamma Delta-T cell compartment is irreversibly "damaged" or "exhausted", this possibly occurring in a tumor-dependent manner. Accordingly, we propose that the use of patient-derived (i.e., autologous) Gamma Delta-T cells for cancer immunotherapy may be undesirable or even impossible. Given this, here we introduce the highly novel concept of using adoptively transferred allogeneic Gamma Delta-T cells for the treatment of cancer or viral infections. In putting forth this highly novel concept, we cite both biological and clinical reasons why the introduction of allogeneic (donor-derived) Gamma Delta-T cells might best be undertaken in the setting of an allogeneic hematopoietic stem cell (HSC) transplant. Thus, contrary to convention, here we propose a highly iconoclastic model in which allogeneic HSC transplantation will not be used as a therapy in itself, but rather as a "therapeutic platform" for the subsequent delivery of therapeutic donor-derived Gamma Delta-T cells. Three aims are proposed. Aim 1 (Proof-of-concept studies): To determine the extent to which donor-derived Gamma Delta-T cells (administered following a fully ablative allogeneic HSC transplant) can eradicate disease in selected mouse tumor models. These studies will be used to establish for the first time, the concept and convention of the "Gamma Delta-T cell donor lymphocyte infusion", heretofore referred to as "Gamma Delta-T cell DLI". Aim 2 (Pre-clinical studies to more closely approximate human clinical applications): To determine the extent to which Gamma Delta-T cell DLI (administered following a nonmyeloablative allogeneic HSC transplant) can eradicate tumors in mice. These studies will be used to extend the concept of the "Gamma Delta-T cell DLI" into a model which is the most likely to be rapidly adapted for clinical use. Aim 3 (Pre-clinical studies to test a second entirely new approach to allogeneic Gamma Delta-T cell-based therapy): To determine the extent to which transient lymphodepletion of tumor-bearing hosts permits the temporary transfer of tumor-reactive allogeneic Gamma Delta-T cells. These never-before proposed models represent a new paradigm for the treatment of cancers, selected virus infections, and possibly, cancers arising as a consequence of infection with oncogenic viruses.